Chromosome 16 inversion is one of the most common chromosome abnormalities in human acute myeloid leukemia. A fusion gene between the core binding factor B (CBFB) gene and the myosin heavy chain 11 (MYH11) gene is generated by this inversion. Using transgenic mouse models we demonstrated recently that CBFB-MYH11 is necessary but not sufficient for leukemogenesis, and that additional genetic changes are needed for full leukemic transformation. We have since been able to identify such cooperating genetic changes in mice with a retroviral insertional mutagenesis approach. CBFB encodes a transcription factors that associates with other nuclear proteins and regulates expression of target genes. Identification of downstream target genes of CBFB will lead to better understanding of its role in leukemogenesis, and potentially new diagnostic and therapeutic targets. We have used the cDNA microarray technology to analyze gene expression changes in leukemic cells harboring the chromosome 16 inversion and have identified potential target genes. Knowledge of normal hematopoiesis will enhance our understanding of leukemogenic process. To understand the role of Cbfb in hematopoiesis and other developmental processes, mice with a Cbfb-GFP knock-in fusion are being generated. Finally, new therapeutic approaches for AML that specifically counteract the function of CBFB-MYH11 will be tested in our established murine leukemia model.